CRISPR-Cas9: A double-edged sword

What if someone handed you a tool and said that you could better the lives of people before their birth by changing their genes? Would you do it?

CRISPR-Cas9 is one such tool. It’s an efficient and effective gene-editing technology that works by tagging a section of DNA with an RNA segment, and then using a protein called Cas9 to cut the DNA at the specified point. Then, the cell’s own DNA machinery works to add or delete DNA.

This technology opens up the pathway to a variety of gene-editing applications, from eliminating HIV in living organisms to creating a potential cure for Huntington’s disease. There is especially high potential for single-gene disorders to be eradicated. For example, promising results from the successful removal of a gene known to cause fatal heart disease from the embryo will not only save lives but also prevent the passing down of the gene.

CRISPR-Cas9 is particularly helpful for discovering which genes affect various disorders or traits. One of the best ways to discover how a gene functions is to remove the gene from an organism and then watch how the organism progresses. An alternative to this method is to simply remove the targeted gene and input mutated versions of it in its place and watch how the changes affect the organism or the cell.

While the ultimate goal is to map out the interplay of the entire human genome, a more realistic aim for the time being may be simply mapping out interactions between just the essential genes. However, it is quite difficult to specify the possible hazards of genetic modification in an organism. For example, genetically modified foods are generally considered to be safe because people eating them have experienced no adverse effects. As one New York Times health columnist writes, “It is not possible to prove a food is safe, only to say that no hazard has been shown to exist,” just as it is impossible to prove that modifying an organism’s working genes is completely without hazard.

Eventually, the hope is that such technology will be able to better people’s quality of life by eradicating disorders and disease. Yet for such a thing to happen, the most efficient method would be to edit the genome in a single-celled embryo so that the correct copy of the gene can propagate throughout the development of the human body. There would be less genetic ground to cover and fewer factors influencing the effects of the gene editing at such an early stage of development. However, there are several risks. Because CRISPR is only about 70 percent effective, there is still a 30 percent risk of failure — thus raising the question of what happens to the embryo if CRISPR doesn’t work. Another risk is that these single-celled embryos have to be modified outside the human body. In order to create a viable human being, it is possible that several rounds of IVF have to be undertaken, which can be emotionally and financially taxing on the couple or person wanting the disease-free child. Finally, there may come a point when some genetic diseases cannot be cured. In one Time article about CRISPR being used in embryos to cure a genetically inherited heart disease, only one of the parents carried the disease. This was necessary because CRISPR used the correct copy of the gene as the master blueprint to correct the mutated gene.

Recently, gene editing was used to create HIV-resistant children in China. This process allowed the father, who is HIV-positive, to have children who would not be infected with HIV. While the scientist who carried out the procedure, He Jianku, says that the baby girls are as healthy as any other newborn, other scientists have pointed out the drawbacks and risks of the procedure. The gene that was knocked out to create HIV resistance made the girls much more susceptible to the West Nile virus than they otherwise would have been. Although CRISPR had been previously used in model organisms such as zebrafish, mice and fruit flies, others believe that the technology was simply too new and too risky to try out on human children. Some question the necessity of the procedure, since current protocols are available that prevent HIV from developing in embryos that have an HIV-positive parent.

While it is certainly possible to genetically modify and ensure seemingly healthy children, should we even do so? It seems that we are already beginning to cross the boundary of artificial selection with application to people. Even if the goal is to ensure a baseline quality of human life by eliminating life-threatening diseases from the genetic pool, this could be already called eugenics.

Eugenics is defined as the “selection of desired heritable characteristics in order to improve future generations, typically in reference to humans.” While this concept often brings to mind the idea of creating more physically attractive generations of people, this can also be interpreted as creating people who are free of genetic disease. This goal would not be so morally objectionable. But take Down syndrome, for instance, which is caused by the presence of an extra chromosome. How would one go about eradicating the syndrome from the population? CRISPR can be used to eliminate an entire chromosome, so if used in a single-celled embryo, Down syndrome could be prevented. One of the most effective methods is utilized by Iceland, a country with a termination rate of Down Syndrome approaching 100 percent. There is widespread prenatal testing combined with selective abortion. In many ways, this is equivalent to removing people with undesirable repositories of DNA in order to keep the gene pool free of undesired traits. Would using a different tool, CRISPR, make something like this less morally objectionable if the principle is the same?

Science aside, there should be a closer look at the laws that govern such experimentation in human embryos for research and possibly implementation. The laws surrounding genetic editing in the human germline vary greatly from country to country. In a 2014 study of the international regulatory landscape of human germline modification, researchers observed 39 countries’ regulations regarding human germline modification. Twenty-nine countries from the study had legally binding bans on human germline modification. The other 10, one of which was the U.S., were ambiguous or had guidelines concerning the use of human embryo modification for research purposes only. The U.S. had a moratorium placed on human germline modification.

It should be noted that the first study demonstrating the use of CRISPR-Cas9 to modify embryos was published in early 2015. Since then, the U.S., which at the time had a moratorium on human germline modification, has since lifted its moratorium without instituting a ban. Since then, the U.S. has allowed modification for strictly research purposes only.

The U.S., at least, shows a loosening of restrictions in regards to human germline modification with the appearance of better technology in the form of CRISPR. As technology advances, do moral standards change? In a hypothetical world, if CRISPR-Cas9 was guaranteed to work in the first single-celled embryo that was successfully implanted and developed into child, should CRISPR be used to edit the human germline for the greater good?

The first wave of revulsion accompanying the thought of editing children’s genomes often stems from the feeling that no one has a right to play God. Nowadays, children are the result of random gene combinations, unaffected by an outside force. Some suffer from dwarfism or Down syndrome. Others are born with muscular dystrophy. Many others come into the world perfectly healthy, aside from a debilitating allergy to peanuts. Most parents strive to give their children the best life possible, gene editing aside. It is generally accepted that genetically modifying children is beyond the role of a parent, whose job is to nurture and protect their child without scientific enhancement. However, there are those who have genetically edited their children for disease prevention purposes. For example, refer back to the couple in China who had chosen to genetically modify their children to be HIV resistant so that the father, who was HIV-positive, would not pass on the virus during pregnancy.

The second often comes from the human aspect. There are mice whose brains can glow, fruit flies with legs protruding from their head and turkeys programmed to gain weight as quickly as possible. Animal testing is deemed necessary because it is unethical to ply humans with highly experimental procedures, according to the Food and Drug Administration. However, there are protections in place with the Animal Welfare Act, Public Health Service policy and the Institutional Animal Care and Use Committee to treat all vertebrates ethically. This means that all invertebrates are denied protection and guidelines for ethical treatment. Already, there is a derogatory attitude present that assumes an inferiority of invertebrates under the law. The assumed superiority of vertebrates affords them protection.

It is highly immoral to test on non-consenting people not only because of the risks and consequences people face, but also because of possible misunderstood ideas and false hopes. This is why when conducting clinical trials for testing new drugs or new procedures, the participants must give their informed consent. Usually, these participants are old enough and mentally mature enough to provide such consent.

Is informed consent truly informed, though? These are clinical trials, the key point being that new compounds are being tested in new environments. It is impossible to summarize the entire list of risks and results, since there may be unseen effects or new side effects with every next iteration of a clinical experiment using a new drug or procedure.

But what about babies? If submitting to the idea that life begins at conception, it is conceivable to call an embryo a person. Therefore, human embryos subject to genetic modification have not given their informed consent at all. Is it perhaps morally better to test on non-viable embryos, then, since they will never have the chance to develop properly? Or is human life sacrosanct, whether or not it can develop beyond the embryonic stage?

One counter argument towards the informed consent of embryos is that of a parental medical authority regarding the health of their children. The age of consent for medical care is usually 18, although some states make exceptions for special circumstances. Therefore, while older children are allowed to make their own decisions regarding certain procedures in some areas due to the ability to consent, younger children and babies are unable to consent to medical procedures, so their parents consent on their behalf. That’s why many babies are vaccinated with the approval of their parents, even though babies can’t give their informed consent. Ostensibly, parents are acting for the good of the child.

However, even if many parents are trying to act in the best interests of their children, they may not succeed at doing so. Take the anti-vaccination movement, for instance. Although the Centers for Disease Control and Prevention say that vaccinating your child is the “safe, proven and effective” method of taking care of a child, there are still people who believe that vaccines can lead to autism. Therefore, they choose not to vaccinate their child, although doing so would mean leaving their children at risk for diseases such as polio and measles. Clearly, not all parents manage to achieve the goals behind their best intentions.

When applied to gene editing, it must be questioned whether or not creating a genetically modified person would be in their best interest. Take the HIV-resistant twin girls into account. While they may be resistant to HIV, they have become vulnerable to West Nile virus. Some genetic diseases can be protective. For example, sickle cell anemia, when expressed heterogeneously, acts to protect the carrier from malaria. First, only individuals who possess both copies of the sickle mutation develop sickle cell anemia, which is when blood cells become abnormally shaped because of abnormal hemoglobin. The body removes such abnormally shaped blood cells which also contain the parasite that spreads malaria if the person was infected, thereby protecting the person from malaria. By removing sickle cell anemia, populations who live in dense mosquito areas would be at the mercy of malaria.

Because of the ethical land mines littering the landscape, one must tread carefully moving towards the future. Few advancements have only had positive effects. One case in point is the one the great advancements that contributed to the modern world — agriculture. Arguably, while agriculture allowed people to settle down and form sedentary communities, it also contributed to the destruction of the environment and the destruction of human health. Genetically modified organisms (GMOs) have allowed the world to grow in leaps and bounds. For example, GMOs allow crops to become more resilient and grown in larger quantities. By applying such a large step to humans, it may be near impossible to fathom the future affected by CRISPR. Whether to ban it or to use it, informed choices must be made with research and a clear mind.

Contact Angela Zhao at angezhao ‘at’ stanford.edu.

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